Novel substituted imidazoles, their preparation and use

ABSTRACT

Novel substituted imidazoles and methods for their preparation are disclosed. These imidazoles, and their salts, exhibit cardioselective β-adrenergic blocking activity, and are useful as antihypertensive agents, cardioprotective agents, antiarrythmic agents, antianginal agents with reduced side effects; e.g., they are devoid of intrinsic sympathomimetic activity.

BACKGROUND OF THE INVENTION

The present invention involves novel imidazoles which have cardioselective β-adrenergic blocking activity and which are useful as antihypertensive agents, cardioprotective agents, antiarrythmic agents, antianginal agents with reduced side effects; e.g., they are devoid of intrinsic sympathomimetic activity (IsA).

A class of pharmaceutical agents, known as β-adrenergic blocking agents, are available and are known to affect cardiac, vascular and pulmonary functions and are mild antihypertensives. Specifically, these agents have the capability of reducing heart rate, without counteracting vasodepression or suppressing bronchodilation. β-adrenergic blocking agents, their chemical structure and activity, are generally disclosed in "Clinical Pharmacology and Therapeutics" 10, 292-306 (1969). Various β-adrenergic blocking agents are also described in such patents as, for example, U.S. Pat. Nos. 3,048,387; 3,337,628; 3,655,663; 3,794,650; 3,832,470; 3,836,666; 3,850,945; 3,850,946; 3,850,947; 3,852,291 and British Pat. No. 1,194,548.

U.S. Pat. Nos. 4,134,983 and 4,199,580 disclose a class of substituted imidazoles which have β-adrenergic blocking activity. While such compounds are effective, their use results in undesirable side affects such as bronchial constriction, muscular fatigue and cold extremities.

SUMMARY OF THE INVENTION

A novel class of substituted imidazoles has been discovered which exhibit cardioselective β-adrenergic blocking activity and are devoid of partial β-agonism i.e., intrinsic sympathomimetic activity (ISA). This new class of substituted imidazoles may also be free from the undesirable side affects associated with the use of the substituted imidazoles disclosed in U.S. Pat. Nos. 4,134,983 and 4,199,580 identified hereinabove. By virtue of their β-blocking activity, the novel imidazoles of the invention also exhibit antihypertensive, cardioprotective, antiarrythmic and antianginal activity. In addition, these novel imidazoles are devoid of undesirable side-effects; e.g., they are devoid of intrinsic sympathomimetic activity (ISA).

DESCRIPTION OF PREFERRED EMBODIMENTS

The compounds of the present invention are represented by the general formula: ##STR1## wherein R and R₁ are independently hydrogen;

C₁ -C₈ linear or branched alkyl; substituted C₁ -C₈ linear or branched alkyl having 1-3 substituents selected from halo (F, Br, Cl), C₁ -C₈ alkoxy, amino, mono- or di-substituted amino wherein the substituent is C₁ -C₈ linear or branched alkyl, aryl of C₆ or C₁₀, aralkyl wherein the aryl is C₆ or C₁₀ and the alkyl group is C₁ -C₃, or which, together with the N atom, forms a 5- or 6-membered ring wherein the 6-membered ring can contain a hetero group selected from O, S, NH or N-lower C₁ -C₈ alkyl;

aryl of C₆ or C₁₀ ;

substituted aryl of C₆ or C₁₀ having 1-5 substituents selected from halo (F, Br, Cl), C₁ -C₈ linear or branched alkyl, or C₁ -C₈ alkoxy;

heteroaryl groups having 5 ring atoms one of which is an O, N-lower C₁ -C₈ alkyl or S heteroatoms;

heteroaryl groups having 6-ring atoms containing 1-2N heteroatoms;

halo (F, Br, Cl);

cyano;

carboxy;

carboalkoxy wherein the alkyl group has up to 8 carbon atoms;

carbamoyl;

mono- or di-substituted carbamoyl wherein the substituent is C₁ -C₈ linear or branched alkyl or which, together with the N atom forms a 5- or 6-membered ring wherein the 6-membered ring can contain a hetero group selected from O, S, NH or N-lower C₁ -C₈ alkyl; ##STR2## wherein Ra is H or C₁ -C₈ alkyl; R₂ is hydrogen;

C₁ -C₈ linear or branched alkyl;

R₃ is aryl or substituted aryl of C₆ to C₁₀ including tetralin and indane having 1-2 substituents selected from halo (F, Br, Cl), C₁ -C₈ alkoxy, alkenyloxy having up to 8 carbon atoms, C₁ -C₈ linear or branched alkyl, C₂ -C₈ alkenyl, cyano, ##STR3## wherein Ra is as defined above; R₄ is hydroxy; ##STR4## wherein Rb is C₁ -C₈ alkyl or aryl of C₆ or C₁₀ ; R₅ is C₁ -C₈ linear or branched alkyl;

C₃ -C₆ cycloalkyl;

substituted C₁ -C₈ alkyl having 1-2 substituents selected from C₁ -C₈ alkoxy, thioalkyl of C₁ -C₈, ureido, substituted ureido having the formula: ##STR5## wherein R₆ and R₇ can independently be hydrogen, C₁ -C₈ alkyl optionally substituted with hydroxy, C₁ -C₈ alkoxy;

unsubstituted or substituted aryl of C₆ or C₁₀ having 1-2 substituents selected from halo, lower C₁ -C₄ alkoxy, and C₁ -C₄ alkyl, or R₆ and R₇ together with the N atom can be joined to form a 6-membered heterocyclic ring containing an additional O, S, NH, or N-lower-C₁ -C₈ alkyl heteroatom;

unsubstituted or substituted aralkyl wherein the alkyl group is linear or branched C₁ -C₈ and the aryl is C₆ having 1-2 substituents selected from C₁ -C₈ alkoxy, hydroxy, halo (F, Br, Cl), C₁ -C₈ alkyl;

heteroaralkyl having 6 ring atoms containing 1-2N heteroatoms and the alkyl is C₁ -C₈ ;

X is CH₂, O or S;

m and n are independently 0, 1, 2 or 3;

provided that when m and n are each zero, X is CH₂ ; and, the pharmacologically acceptable acid addition salts thereof.

Compounds of particular interest have the formulae: ##STR6## wherein R-R₅, X, m and n are as defined above.

Examples of suitable R and R₁ aryl groups include pentafluorophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 4-ethoxy-3-chlorophenyl, 4-methyl-2,3-dichlorophenyl, 2-propylphenyl, 4-isopropylphenyl, phenyl, 2-methoxy-4-methylphenyl, 2,5-dimethoxy-3,4-dimethylphenyl, and the like.

Illustrative R and R₁ 5-membered heteroaryl groups include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, N-methyl-2-pyrrolyl, and the like.

Exemplary R and R₁ 6-membered heteroaryl groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl and the like.

With respect to the R₃ aryl groups, the imidazole alkyl group and the hydroxy propoxy amine group are situated ortho, meta or para to each other. Accordingly, suitable R₃ aryl groups include 2,3-dichloro-1,4-phenylene, 3-chloro-1,4-phenylene, 1,4-naphthalene, 3-allyloxy-1,4-phenylene, 3-allyl-1,4-phenylene, 3-cyano-1,4-phenylene, 3-acetyl-1,4-phenylene, 5,6,7,8-tetrahydro-1,4-naphthalene, 5,6-dihydro-1,4-indane, 3-methyl-1,4-phenylene, 2,3-dimethyl-1,4-phenylene, 4-ethyl-1,3-phenylene, 4-bromo-1,3-phenylene, 5-chloro-1,2-phenylene, 1-pentanone-1-(2,5-phenylene), 4-n-butoxy-1,3-phenylene, 3-fluoro-1,4-phenylene, and the like.

Illustrative aryl groups in the R₅ aralkyl moiety include 3,4-dimethoxyphenyl, 3,4-di-n-butoxyphenyl, 3,4-methylenedioxyphenyl, 3-hydroxy-4-methoxyphenyl, 3-methoxy-4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 2-hydroxyphenyl, 3,4-dichlorophenyl, 3,5-dibromophenyl, 3-hydroxy-4-chlorophenyl, 4-chloro-3-hydroxyphenyl, 4-fluorophenyl, 4-hexyloxyphenyl, 3-methylphenyl, 3,4-dimethylphenyl, and the like.

The 6-membered heteroaryl groups for the R₅ heteroaralkyl groups include the same 6-membered heteroaryl groups described above for R and R₁.

Illustrative R₆ and R₇ groups include methyl, ethyl, n-butyl, hydroxyethyl, methoxybutyl, phenyl, benzyl, and the like and when R₆ and R₇ are joined together with the N-atom, they form such hetero rings as ##STR7## and the like.

Preferred are those compounds of Formula I wherein:

R and R₁ are independently:

hydrogen;

C₁₋₈ linear or branched alkyl;

halo;

heteroaryl groups having 5-ring atoms, one of which is an O, N--C₁ -C₈ -loweralkyl, or S hetero group;

carboalkoxy wherein the alkyl group has up to 8 carbon atoms;

CF₃ ;

carbamoyl

cyano; ##STR8## wherein R_(a) is hydrogen or C₁ -C₈ alkyl; unsubstituted or substituted aryl of C₆ having 1-5 substituents selected from halo, C₁ -C₈ linear or branched alkyl, or C₁ -C₈ alkoxy; heteroaryl groups having 6-ring atoms containing 1-2N heteroatoms;

R₂ is hydrogen;

C₁ -C₈ linear or branched alkyl;

R₃ is unsubstituted or substituted aryl of C₆ or C₁₀ having 1-2 substituents selected from halo, C₁ -C₈ alkoxy, alkenyloxy having up to 8 carbon atoms; C₁ -C₈ linear or branched alkyl, cyano, ##STR9## wherein R_(a) is as defined above; R₄ is hydroxy;

R₅ is C₃ -C₅ cycloalkyl;

C₁ -C₈ linear or branched alkyl;

unsubstituted or substituted aralkyl wherein the alkyl is linear or branched C₁ -C₈ and the aryl is C₆ or C₁₀ having 1-2 substituents selected from C₁ -C₈ alkoxy, hydroxy, halo, C₁ -C₈ alkyl; heteroaryl having 6-ring atoms containing 1-2N heteroatoms;

X is oxygen or CH₂ ; and,

m and n are independently 0-2 provided that at least one of m or n is 1.

More preferred are compounds of Formula I wherein:

R and R₁ are independently

hydrogen;

C₁ -C₈ linear or branched alkyl;

halo;

heteroaryl groups having 5-ring atoms, one of which is an O or S heteroatom;

carboalkoxy wherein the alkyl group has up to 8 carbon atoms;

CF₃ ; ##STR10## wherein R_(a) is C₁ -C₃ alkyl; R₂ is hydrogen;

R₃ is 1,4-phenylene;

R₄ is hydroxy;

R₅ is C₃ -C₅ cycloalkyl; p1 C₁ -C₈ linear or branched alkyl;

unsubstituted or substituted aralkyl wherein the alkyl is linear or branched C₁ -C₈ and the aryl is C₆ having 1-2 C₁ -C₈ alkoxy substituents;

X is CH₂ ; and,

m and n are independently zero or 1.

The compounds of the present invention include all the optical isomer forms. In other words, the compounds include mixtures containing the optical isomers such as racemic mixtures, diastereomeric mixtures, as well as the individual optical isomers.

The compounds of the present invention also include the N-oxides and the non-toxic pharmacologically acceptable acid addition salts of the present imidazoles. The acid addition salts are prepared by treating the compounds of the invention with an appropriate amount of a suitable organic or inorganic acid. Examples of useful organic acids are carboxylic acids such as maleic acid, tartaric acid, acetic acid, pamoic acid, oxalic acid, propionic acid, salicylic acid, succinic acid, citric acid, malic acid, isethionic acid, and the like; useful inorganic acids are hydrohalo acids such as HCl, HBr and HI, sulfuric acid, H₃ PO₄, and the like.

Compounds of the present invention may be prepared by any convenient method; however, the methods actually utilized will depend upon the R-R₅ substituents as well as X, m and n. In the methods described below the R-R₅ groups, X, m and n, are as defined above unless otherwise indicated. Also, unless otherwise indicated, the starting materials employed are known in the literature, are commercially available, or can be prepared by methods known to those skilled in the art. ##STR11##

As shown in Method A, α-haloketone 2 is reacted with amidine 3 in a suitable solvent such as chloroform, acetonitrile, tetrahydrofuran (THF), acetone, methylene chloride, and the like, preferably chloroform, at a temperature of from about 0° C. to the reflux temperature of the solvent, preferably at ambient temperature, over a period of about 1-48 hours to obtain imidazole 10 wherein R₈ is a suitable protecting group such as methyl, benzyl, and the like. In this Method, amidine 3 is prepared from a nitrile using standard procedures described in the literature. ##STR12##

In Method B, glyoxal 4 is reacted with aldehyde 5 using a suitable alcohol solvent such as methanol, ethanol, and the like, or a suitable solvent such as THF, acetonitrile, dimethylformamide (DMF), and the like, preferably methanol to obtain imidazole 10 wherein R₈ is as defined for Method A. ##STR13##

To obtain imidazole 10 by Method C, amidoxime 7 (prepared from the corresponding nitrile by reaction with hydroxylamine) is treated with a substituted propiolate ester 6 in an alcohol solvent (e.g., CH₃ OH, EtOH) or a suitable solvent such as acetonitrile, THF, acetone, DMF, and the like, preferably an alcohol, to obtain olefin 8. In olefin 8, when R₁ =H, there is obtained a mixture of cis and trans isomers and when R₁ =alkyl or aryl, there is obtained a mixture of E and Z isomers. Olefin 8 is then treated in a solvent such as DMF, dimethylsulfoxide (DMSO), diphenylether, xylene, and the like, at temperatures of about 0° C. to the reflux temperature of the solvent, preferably about 190° C. in diphenylether over a period of about 1/2 to 2 hours to yield imidazole 10 (R₁ =H, alkyl, aryl; R₂ =CO₂ R₉). ##STR14##

In Method D, imidazole 9 (R₁ =H and R₈ is as defined in Method A) is treated with a halogenating agent such as Br₂, Cl₂, N-chlorosuccinimide, N-bromosuccinimide, potassium chlorate, sodium hypochlorite, cyanogen chloride, cyanogen bromide, pyridine perbromide, and the like, in a solvent such as chloroform, acetonitrile, DMF, THF, water, and the like at 0° C. to the reflux temperature of the solvent over a period of about 15 minutes to 24 hours to obtain imidazole 10. ##STR15##

As shown in Method E, imidazole 10 (R₈ =CH₃) is treated with any ether cleaving reagent such as 48% HBr in acetic acid, pyridine-HCl, AlCl₃ /C₆ H₆, and BBr₃ /CH₂ Cl₂ at 0° to the reflux temperature of the solvent for about 1-24 hours to obtain imidazole phenol 11 (X=CH₂). Imidazole 10 (R₈ =CH₂ C₆ H₅) is treated with a suitable solvent such as an alcohol (CH₃ OH, EtOH, and the like) or acetic acid at ambient temperature for a period of about 15 minutes to about 15 hours in the presence of a suitable catalyst such as 10% Pd on carbon, platinum oxide, and the like, at a pressure of up to about 60 psi to afford imidazole 11 (X=CH₂ or X=O when m and n are >1). ##STR16##

For Method F, imidazole phenol 11 is prepared as described in Method E above and is then reacted with the oxazolidine tosylate or any other suitable leaving group such as mesylate, triflate, or iodide, and a base such as sodium hydride, sodium methoxide, sodium hydroxide, potassium t-butoxide, and the like, preferably sodium hydride, in an appropriate solvent such as DMSO, DMF, toluene, methanol, water, and the like, preferably DMF, at 0° C. to the reflux temperature of the solvent over a period of about 1-48 hours, preferably 110° for 18 hours, to obtain an oxazolidine intermediate.

The oxazolidine intermediate is then subjected to acid hydrolysis using such acids as aqueous HCl, H₂ SO₄, acetic acid, and the like, at 0° to the reflux temperature of the solvent for about 15 minutes to 15 hours, preferably in 1N HCl for 15 minutes at 100°, to obtain imidazole 1. ##STR17##

In Method G, imidazole phenol 11 is first reacted with a base and the oxazolidone mesylate [prepared according to the methods described in Canadian Pat. No. 965,787] or any other suitable leaving group such as tosylate, triflate or iodide, preferably using NaH as base, DMSO as solvent at 60° C. for 2 hours, followed by treatment with an aqueous base such as sodium hydroxide, potassium hydroxide, and the like, at a strength of 1-40% in an appropriate solvent such as methanol, ethanol, acetone, THF, and the like (preferably 10% NaOH--EtOH, 1:1), at the reflux temperature of the solvent over a period of about 15 minutes to 24 hours, preferably for 2 hours at 100° C., to afford imidazole 1. ##STR18##

As shown in Method H, epoxide 12 can be prepared by reaction of phenol 11 with epichlorohydrin in an aqueous base. Alternatively, phenol 11 can be reacted with acetonide (A) containing a suitable leaving group such as mesylate, tosylate, triflate or iodide in a suitable solvent as described in Method F above to provide compound (B). Reaction of compound (B) with an alkylating agent (R₂ I) provides type (C) compounds where R₂ is an alkyl group. Hydrolysis of compound (B) in a mineral acid as described in Method E, followed by mesylation of the primary alcohol and subsequent treatment with NaOCH₃ yields epoxide 12. Treatment of epoxide 12 with an amine (R₅ NH₂) in an appropriate solvent (THF, methylene chloride, methanol, isopropyl alcohol; preferably a mixture of methylene chloride and methanol) at about 0° C. to reflux temperature of the solvent for about 1 to 48 hours affords imidazole 1.

When compound (C) is used in place of compound (B), imidazoles 1 are obtained where R₂ is an alkyl group. ##STR19##

In Method I, glyoxal 4 is reacted with oxazolidine protected aldehyde 13 under the same conditions as described in Method B above, and is then subjected to acid hydrolysis as described in Method F above to obtain imidazole 1. ##STR20##

For Method J, the same procedure is followed as described in Method B for reacting glyoxal 4 with oxazolidine protected aldehyde 14 followed by base hydrolysis as described in Method G to obtain imidazole 1. ##STR21##

Following the same procedures as described in Method G, imidazole 17 is prepared from the reaction of imidazole 15 and oxazolidone 16 after base hydrolysis.

Imidazole 17 is then treated in an appropriate solvent such as dilute mineral acid (HCl, H₂ SO₄, H₃ PO₄ and the like) or alcohol/acetic acid mixtures, preferably in CH₃ OH--AcOH, at 0° C. to the reflux temperature of the solvent, preferably 2 hours in refluxing CH₃ OH, to yield imidazole 1. ##STR22##

Following the same procedures as described in Method G, imidazole 18 and oxazolidone 19 yielded imidazole 20 which was then treated as described in Method E (R₈ =CH₂ C₆ H₅) to remove the CH₂ C₆ H₅ protecting group and afford imidazole 1.

In Methods K and L, compounds 16 and 19 can also be prepared as the corresponding oxazolidines. The resulting compounds can then be subjected to acid hydrolysis to cleave the protected oxazolidine ring to afford imidazole 1.

The Methods illustrated hereinabove permit preparation of single optical isomers and/or racemates or diastereomers. In the foregoing Methods, the oxazolidines were prepared according to the processes disclosed and described in U.S. Pat. Nos. 3,892,744 and 4,051,144.

The compounds of the present invention are active as cardioselective β-adrenergic blocking agents, are useful as antihypertensive, cardioprotective, antiarrythmic, and antianginal agents and are devoid of intrinsic sympathomimetic activity (ISA).

The β-adrenergic blocking activity (β-blockade) of the present compounds was determined by measuring the ability of representative compounds to block isoproterenol induced tachycardia without counteracting vasodepression or suppressing bronchodilatation in animals. Administration of the imidazoles of the present invention (generally as an acid addition salt) was used for this evaluation.

Representative compounds of Formula I which exhibited β-adrenergic blocking and antihypertensive activity are listed below:

(a) (S)-2-{p-[3-(3,4-dimethoxyphenylethylamino)-2-hydroxypropoxy]phenylmethyl}-4-methylimidazole;

(b) (S)-2-[p-(3-t-butylamino-2-hydroxypropoxy)phenylmethyl]-4-(2-thienyl)imidazole;

(c) (S)-2-[p-(3-t-butylamino-2-hydroxypropoxy)phenylmethyl]-4-methylimidazole;

(d) (S)-1-(4-bromoimidazol-2-yl)-2-{p-[3-(3,4-dimethoxy-phenylethylamino)-2-hydroxypropoxy]phenyl}ethane;

(e) (S)-1-[4-(2-thienyl)imidazol-2-yl]-2-{p-[3-(3,4-dimethoxyphenylethylamino)-2-hydroxypropoxy]phenyl}ethane;

(f) (S)-4-bromo-2-[p-(3-isopropylamino-2-hydroxypropoxy)phenylmethyl]imidazole;

(g) (S)-2-{p-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]phenylmethyl}-4-acetylimidazole;

(h) (S)-3-[3,4-dimethoxyphenylethylamino]-2-hydroxy-1-[4-[2-imidazolylmethoxymethyl]phenoxy]propane;

(i) (S)-3-(3,4-dimethoxyphenylethylamino)-2-hydroxy-1-[4-(2-imidazolylmethoxy)phenoxy]propane.

The β-adrenergic blocking effectiveness of the compounds of the present invention indicates that they are also useful to treat humans suffering from undesirable conditions such as angina pectoris or certain arrhythmias which are known to be amenable to treatment with β-adrenergic blocking agents. Thus, the compounds of the invention are useful as antihypertensive, cardioprotective, antiarrythmic, and antianginal agents with reduced side effects; e.g., they are devoid of ISA. Furthermore, the cardioselective nature of the compounds of the present invention offers the advantage of limiting blockade to only the β₁ receptors; i.e., those which control heart rate. Thus, these β-blocking agents are also useful to control tachycardia which may be drug induced (as by isoproterenol) or brought about by physiological conditions, reduce intraocular pressure in the treatment of glaucoma, and inhibit renal renin secretion.

For use as antihypertensive and/or β-adrenergic blocking agents, the present compounds can be administered orally or parenterally; i.e., intravenously, interperitoneally, etc. and in any suitable dosage form. The compounds may be offered in a form (a) for oral administration; e.g., as tablets, in combination with other compounding ingredients customarily used such as talc, vegetable oils, polyols, benzyl alcohols, gums, gelatin, starches and other carriers; dissolved or dispersed or emulsified in a suitable liquid carrier; in capsules or encapsulated in a suitable encapsulating material; or (b) for parenteral administration; e.g., dissolved or dispersed in a suitable liquid carrier or emulsified or (c) for transdermal application.

It is often advantageous to administer compounds of this invention in combination with angiotensin converting enzyme inhibitors and/or antihypertensives and/or diuretics. For example, the compounds of this invention can be given in combination with such compounds as enalapril, hydrochlorothiazide, hydralazine hydrochloride, methyldopa, and the like, as well as admixtures and combinations thereof.

The ratio of active compound of the invention to compounding ingredients; i.e., carrier, diluent, etc., and/or other combination compounds will vary as the dosage form requires. Whatever dosage form is used, the amount of compound of the present invention administered should be sufficient to effect (a) a reduction in blood pressure of the patient suffering from hypertension and/or (b) desirable level of β-blockade in the patient. Generally, doses of the present compounds can be administered in amounts of from about 1 mg to about 1 g and preferably from about 5 to about 500 mg per day. Dosage may be single or multiple depending on the daily total required and the unit dosage.

Following are examples illustrating representative pharmaceutical formulations containing imidazoles of the present invention. Conventional techniques are used to prepare these formulations

    ______________________________________                                         INGREDIENT             AMOUNT (Mg.)                                            ______________________________________                                         TABLET FORMULATION                                                             (S)--2-{p-[3-(3,4-dimethyoxyphenethyl-                                                                40.0                                                    amino)-2-hydroxypropoxy]-phenylmethyl}-                                        4-acetylimidazole                                                              calcium phosphate      120.0                                                   lactose                50.0                                                    starch                 23.5                                                    magnesium stearate     1.5                                                     CAPSULE FORMULATION                                                            (S)--2-[p-(3-t-butylamino-2-hydroxy-                                                                  250                                                     propoxy)phenylmethyl]-4-(2-thienyl)                                            imidazole                                                                      lactose, U.S.P.        93                                                      talc                   7                                                       OCULAR FORMULATION                                                             (S)--1-(4-bromoimidazol-2-yl)-2-                                                                      15.0                                                    {p-[3-(3,4-dimethoxyphenylethylamino)-                                         2-hydroxypropoxy]phenyl}ethane                                                 sodium phosphate monobasic.2H.sub.2 O                                                                 6.10                                                    dibasic sodium phosphate.12H.sub.2 O                                                                  16.80                                                   benzalkonium chloride  0.10                                                    sodium hydroxide q.s. ph                                                                              6.8                                                     water for injection q.s. ad.                                                                          1.0 ml                                                  LIQUID SUSPENSION                                                              (S)--2-{p-[3-(3,4-dimethoxyphenylethyl-                                                               5.0                                                     amino)-2-hydroxypropoxy]phenylethyl}-4-                                        (2-thienyl)imidazole dihydrochloride                                           dihydrate                                                                      Veegum H.V.            3.0                                                     methyl parable         1.0                                                     kaolin                 10.0                                                    glycerin               250.0                                                   water, q.s.            1 liter                                                 ______________________________________                                    

The following examples illustrate preparation of representative imidazoles of the present invention. Unless otherwise indicated, all parts and percentages are by weight, all temperatures are in degrees Celsius, and all analyses were computed to within 0.4%.

EXAMPLE 1 (S)-2-{p-[3-(3,4-Dimethoxyphenethylamino)-2-hydroxypropoxy]phenylmethyl}-4-methylimidazole dihydrochloride (III) Step A: 2-(p-Methoxyphenylmethyl)-4-methylimidazole (I)

A solution of chloroacetone (5.27 g, 0.057 m) in CHCl₃ (90 mL) was added to a stirred suspension of 4-methoxyphenylacetamidine (28.0 g, 0.17 m) in CHCl₃ (470 mL) over 1 hour. The mixture was heated at reflux for 75 minutes and then stirred at ambient temperature for 43 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The oily residue was chromatographed on alumina and eluted with CHCl₃ to yield 8.14 g (71%) of I; m.p. 108°-109° C. (CHCl₃ -C₆ H₁₄).

Anal. Calc'd. for C₁₂ H₁₄ N₂ O:C, 71.26; H, 6.98; N, 13.85. Found: C, 71,01; H, 7.07; N, 13.60.

Step B: 2-(p-Hydroxyphenylmethyl)-4-methylimidazole (II)

A mixture of 2-(p-methoxyphenylmethyl)-4-methylimidazole (5.0 g, 0.025 m), glacial acetic acid (37 mL) and 48% hydrobromic acid (125 ml) was heated at reflux for 5 hours. The solution was concentrated under reduced pressure and the oily residue was stirred in saturated sodium bicarbonate solution (55 mL) for 17 hours. The solid was collected and dried to yield 4.22 g (90%) of II; m.p. 193°-194° C. (CH₃ CN).

Anal. Calc'd. for C₁₁ H₁₂ N₂ O: C, 70.19; H, 6.43; N, 14.89. Found; C, 70.08; H, 6.60; N, 15.05

Step C: (S)-2-{p-[3-(3,4-Dimethoxyphenethylamino)-2-hydroxypropoxy]-phenylmethyl}-4-methylimidazole dihydrochloride (III)

Sodium hydride (0.78 g, 0.0163 m, 50% dispersion in mineral oil) was added to a solution of 2-(p-hydroxybenzyl)-4-methylimidazole (3.00 g, 0.016 m) in dimethylsulfoxide (40 mL) and the mixture heated at 60° C. for 15 minutes. A solution of (S)-3-(3,4-dimethoxyphenyl)ethyl-5-(hydroxymethyl)oxazolid-2-one mesylate (5.86 g, 0.0163 m) in dimethylsulfoxide (40 mL) was added and the mixture heated at 60° C. for 3 hours. It was then poured into H₂ O (400 mL), the pH adjusted to 10 with 40% NaOH solution and extracted with CH₂ Cl₂ (3×150 mL). After washing with H₂ O and drying, the solvent was concentrated under reduced pressure. The residue was dissolved in ethanol (100 mL), 10% NaOH solution (100 mL) added and the mixture heated at reflux under N₂ for 2 hours. Ethanol was evaporated under reduced pressure, H₂ O (200 mL) was added and the mixture extracted with CH₂ Cl₂ (3×150 ml). The solvent was evaporated under reduced pressure and the residue chromatographed on silica gel, eluting with 5% MeOH-CHCl₃ saturated with NH₃. The impure product was rechromatographed on silica gel and eluted with 25% ethyl acetate/25% n-butanol/25% acetic acid/25% H₂ O. After combining and concentrating the appropriate fractions under reduced pressure, the residue was distributed between saturated sodium bicarbonate solution (50 mL) and CHCl₃ (100 mL), the organic layer washed with H₂ O, dried and concentrated under reduced pressure to yield 2.68 g (39%) of oily product which was crystallized as the dihydrochloride salt III; m.p. 201.5°-203.5° C. (EtOH--Et₂ O)

Anal. Calc'd. for C₂₄ H₃₁ N₃ O₄.2HCl: C, 57.83; H, 6.67; N, 8.43. Found: C, 57.57; H, 6.79; N, 8.45

EXAMPLE 2 (S)-2-[p-(3-t-Butylamino-2-hydroxypropoxy)phenylmethyl]-4-(2-thienyl)imidazole dihydrogen maleate salt (IV)

Sodium hydride (0.86 g, 0.018 m, 50% dispersion in mineral oil) was added to a stirred solution of 2-(p-hydroxyphenylmethylbenzyl)-4-(2-thienyl)imidazole (4.45 g, 0.017 m) in dimethylsulfoxide (40 ml) and the mixture was heated at 60° C. for 15 minutes under nitrogen. A solution of (S)-3-t-butyl-5-(hydroxymethyl)oxazolid-2-one mesylate (4.52 g, 0.018 m) in dimethylsulfoxide (40 mL) was added and the mixture heated at 60° C. for 19 hours. After cooling, the mixture was poured into cold H₂ O (400 mL), rendered alkaline with 40% sodium hydroxide solution and extracted with CH₂ Cl₂ (3×120 mL). After washing with H₂ O and drying over Na₂ SO₄, the solvent was evaporated under reduced pressure. The residue was refluxed under N₂ for 71 hours in a mixture of ethanol (110 mL) and 10% sodium hydroxide solution (110 mL). Ethanol was evaporated under reduced pressure, H₂ O (225 mL) added and the mixture extracted with CH₂ Cl₂ (3×150 mL). After washing with H₂ O and drying over Na₂ SO₄, solvent was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 10% MeOH--CHCl₃ saturated with ammonia, to yield product which was crystallized as the dihydrogen maleate salt IV; m.p. at 122°-125° C. (CH₃ OH--Et₂ O).

Anal. Calc'd. for C₂₁ H₂₇ N₃ O₂ S.2C₄ H₄ O₄ : C, 56.39; H, 5.71; N, 6.80 Found: C, 56.49; H, 6.09; N, 6.97

EXAMPLE 3 (S)-2-[p-(3-t-Butylamino-2-hydroxypropoxy)phenylmethyl]-4-methylimidazole dihydrogen maleate salt (V)

Sodium hydride (0.52 g, 0.0108 m) 50% dispersion in mineral oil) was added to a stirred solution of II (2.00 g, 0.0106 m) in dimethylsulfoxide (26 mL) and the mixture heated at 60° C. for 10 minutes under nitrogen. A solution of (S)-3-t-butyl-5-(hydroxymethyl)oxazolid-2-one mesylate (2.72 g, 0.0108 m) in dimethylsulfoxide (26 mL) was added and the mixture was heated at 60° C. for 3 hours. The mixture was cooled, poured into cold H₂ O (260 mL), rendered alkaline with 40% sodium hydroxide solution and extracted it CH₂ Cl₂ (3×80 mL). The extract was washed with H₂ O, dried over Na₂ SO₄ and concentrated under reduced pressure. The residue was heated at reflux in EtOH (75 mL) and 10% NaOH solution under nitrogen for 69.5 hours. Solvent was evaporated under reduced pressure, H₂ O (130 mL) added to the residue and extracted with CH₂ Cl₂ (3×100 mL). The combined extracts were washed with H₂ O, dried over Na₂ SO₄ and evaporated under reduced pressure. The residue was crystallized as the dihydrogen maleate salt V; m.p. 126°-129° C. (EtOH--Et₂ O)

Anal. Calc'd. for C₁₈ H₂₇ N₃ O₂.2C₄ H₄ O₄ : C, 56.82; H, 6.42; N, 7.65 Found: C, 56.62; H, 6.58; N, 7.30

EXAMPLE 4 (S)-1-(4-Bromoimidazol-2-yl)-2-{p-[3-(3,4-dimethoxyphenyl-ethylamino)-2-hydroxypropoxy]phenyl}ethane dihydrochloride (IX) Step A: 2-(p-Methoxyphenylethyl)-4-trifluoromethylimidazole (VI)

A mixture of 1,1-dibromo-3,3,3-trifluoroacetone (27. g, 0.1 mole) sodium acetate trihydrate (27.2 g, 0.2 mole), and water (110 mL) was stirred and heated on the steam bath for 30 minutes. The resulting solution was cooled in an ice bath and 3-(p-methoxyphenyl)propanal (16.5 g, 0.1 mole), CH₃ OH (520 mL), and concentrated NH₄ OH (140 mL) were added. The mixture was stirred at room temperature. After 16 hours, CH₃ OH was stripped from the solution under reduced pressure and the solid product collected from the aqueous residue. Recrystallization of the dried solid yielded 12.53 g (46%) of VI; m.p. 146°-148° C. (EtOAc-Pet. Ether).

Analysis calc'd. for C₁₃ H₁₃ F₃ N₂ O: C, 57.78; H, 4.85; N. 10.37. Found: C, 57.72; H, 4.98; N, 10.17.

Step B: 4-Bromo-2-(p-methoxyphenylethyl)-5-trifluoromethylimidazole (VII)

N-Bromosuccinimide (5.4 g, 0.03 mole) was added to a solution of VI (8.1 g, 0.03 mole) in CH₃ CN (150 mL) and the mixture stirred at room temperature. After 18 hours, the solution was evaporated to dryness in vacuo. The residue was partitioned between CHCl₃ and H₂ O. Evaporation of the washed and dried CHCl₃ extract under reduced pressure left 10.5 g (quant.) of VII; m.p. 104°-106° C. (CHCl₃ --C₆ H₁₄).

Analysis calc'd. for C₁₃ H₁₂ BrF₃ N₂ O:C, 44.72; H, 3.47; N, 8.02. Found: C, 45.14; H, 3.38; N, 8.16.

Step C: 4-Bromo-2-(p-hydroxyphenylethyl)imidazole (VIII)

A solution of VII (10.5 g, 0.03 mole) in EtOH (110 mL) and 10% aq. NaOH (90 mL) was heated at reflux for 4 hours and then evaporated to dryness in vacuo. The residue was suspended in H₂ O (120 mL), treated with conc. HCl (230 mL), and the mixture heated at reflux with stirring. After 24 hours, the mixture was cooled in an ice bath.

The precipitate was collected, dried, and chromatographed on silica gel. The product was eluted with 90CHCl₃ --10CH₃ OH saturated with conc. NH₄ OH to yield 0.8 g (10%) of VIII; m.p. 191°-193° C.

Analysis calc'd. for C₁₁ H₁₁ BrN₂ O: C, 49.45; H, 4.15; N, 10.49. Found: C, 49.15; H, 4.27; N, 10.40.

Step D: (S)-1-(4-Bromoimidazol-2-yl)-2-{p-[3-(3,4-dimethoxyphenylethylamino)-2-hydroxypropoxy]phenyl}ethane dihydrochloride (IX)

Under N₂, sodium hydride (110 mg, 2.8 mmole, 60% oil dispersion) was added to a stirred solution of VIII (750 mg, 2.8 mmole) in dry DMSO (10 mL). The mixture was heated at 60° C. After 15 minutes when the hydrogen evolution was complete, (S)-3-(3,4-dimethoxyphenylethyl)-5-hydroxymethyloxazolid-2-one mesylate (900 mg, 2.5 mmole) was added in one portion. The resulting mixture was stirred at 65° C. for 6 hours. After cooling, the mixture was quenched in ice water (50 mL) and the gummy solid product extracted into CH₂ Cl₂. Evaporation of the washed and dried CH₂ Cl₂ extract left the intermediate oxazolidone derivative as a glass (1.3 g). The solid was dissolved in absolute EtOH (25 mL) and aqueous NaOH (15 ml, 10%) and the mixture heated at reflux for 3 hours. After concentration under reduced pressure, the residue was partitioned between CH₂ Cl₂ and H₂ O. The washed and dried CH₂ Cl₂ extract was evaporated to dryness to yield 880 mg of the oily crude product that was purified by chromatography on silica gel, eluting with 25 EtOAc-5n-BuOH-5HOAc-3H₂ O. The partially purified base was converted to the dihydrochloride XI to yield 77 mg (4.8%), m.p. 181°-183° C. (i-PrOH).

Analysis calc'd. for C₂₄ H₃₀ BrN₃ O₄ (+2HCl): C, 49.93; H, 5.59; N, 7.28. Found: C, 49.81; H, 5.72; N, 7.17.

EXAMPLE 5 (S)-2-{p-[3-(3,4-Dimethoxyphenylethylamino)-2-hydroxypropoxy]phenylmethyl}-4-(2-thienyl)imidazole dihydrobromide dihydrate (XII) Step A: 2-(p-Methoxyphenylmethyl)-4-(2-thienyl)imidazole (X)

To a solution of 4-methoxyphenylacetamine (14 q, 0.085 mL) in CHCl₃ (200 mL) was added dropwise with stirring at room temperature a solution of (α-bromoacetyl)thiophene in CHCl₃ (75 mL). After 18 hours, the mixture was concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with CHCl₃ saturated with NH₃ to yield 5.5 g of X (72%).

¹ H NMR (Me₂ SO-d₆) δ3.55 (3H, S), 3.8 (2H, bs), 6.6 (2H, d, J=8), 7.0 (6H, m).

Step B: 2-(p-Hydroxyphenylmethyl)-4-(2-thienyl)imidazole (XI)

A mixture of X (5.5 g, 0.02 mol), AcOH (30 mL) and 48% HBr (100 mL) was heated at reflux for 4 hours and then concentrated to dryness. The solid was stirred overnight with a solution of concentrated NaHCO₃ and the suspension filtered off to yield 2.7 g of XI (52%); m.p. 189°-91° C. (H₂ O--CH₃ CN).

Analysis calc'd for C₁₄ H₁₂ N₂ OS: C, 65.60; H, 4.72; N, 10.93. Found: C, 65.62; H, 4.65; N, 10.93.

Step C: (S)-2-{p-[3-(3,4-Dimethoxyphenylethylamino)-2-hydroxypropoxy]phenylmethyl}-4-(2-thienyl)imidazole dihydrochloride dihydrate (XII)

Prepared as described in Example 1 except the tosylate of (S)-2-phenyl-3-(3,4-dimethoxyphenylethyl)-5-(hydroxymethyl)oxazolidine was utilized instead of the mesylate of (S)-3-(3,4-dimethoxyphenylethyl)-5-(hydroxymethyl)oxazolid-2-one. The intermediate oxazolidine was hydrolyzed in 1N HCl, the reaction basified to pH>10, and extracted with CHCl₃ (3X). The organic extracts were dried, filtered, and concentrated to dryness. The residue was chromatographed on silica gel eluting with 2% CH₃ OH--CHCl₃ saturated with NH₃. The product XII was crystallized as the HBr salt (5%); m.p.. 231°-233° C.

Analysis calc'd for C₂₇ H₃ N₃ O₄ S(2HBr: C, 54.54; H, 6.38; N, 6.82. Found: C, 54.43; H, 6.28; N, 6.61.

EXAMPLE 6 (S)-4-Bromo-2-[p-(3-isopropylamino-2-hydroxypropoxy)phenylmethyl]imidazole (XVII) Step A: 2-(p-Methoxyphenylmethyl)imidazole (XIII)

A mixture of p-methoxyphenylacetaldehyde (24.6 g, 0.16 mole) and 40% glyoxal in water (70 mL) was stirred in CH₃ OH (300 mL) and treated with concentrated NH₄ OH (150 mL). The resulting solution was stirred at room temperature. After 18 hours, CH₃ OH was stripped from the solution under reduced pressure. The residue was partitioned between CHCl₃ and H₂ O, filtering from insoluble black tar. Evaporation of the washed and dried CHCl₃ extract under reduced pressure left the crude product (25.5 g) as an oily black solid. This was extracted with 3×600 mL of boiling H₂ O, filtering from viscous black oil through glass wool. The combined filtrates deposited 8.0 g of slightly oily brown solid on cooling. Trituration with CH₃ CN yielded 6.15 g (20%) of XIII; m.p. 158°-160° C. (CH₃ CN).

Analysis calc'd for C₁₁ H₁₂ N₂ O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.00; H,, 6.38; N, 15.26.

Step B: 2-(p-Hydroxyphenylmethyl)imidazole (XIV)

A solution of XIII (6.6 g, 0.035 mole) in glacial HOAc (40 mL) and 48% HBr (110 mL) was stirred at reflux for 7 hours and then evaporated to dryness in vacuo. The residue was stirred with saturated NaHCO₃ (200 mL) for 16 hours at room temperature. The aqueous phase was decanted from the residue which again was stirred with saturated NaHCO₃ for 2 hours. This aqueous phase was decanted and the residue was extracted with 3×100 mL of boiling H₂ O filtering from insoluble material. All of the aqueous phases were combined and evaporated to dryness in vacuo. The residue was extracted with 3×100 mL of CHCl₃ --MeOH (60:40), filtering from inorganic material. Evaporation of the filtrate left the crude product as an oily brown solid that was purified by chromatography on silica gel, eluting with 90CHCl₃ --10MeOH--1H₂ O; to yield XIV (74%); m.p. 188°-190° C. (CH₃ CN).

Analysis calculated for C₁₀ H₁₀ N₂ O: C, 68.95; H, 5.79; N, 16.08. Found: C, 68.97; H, 5.94; N, 16.21.

Step C: (S)-2-[p-(3-Isopropyloxazolid-2-on-5-yl)methoxy]phenylmethylimidazole (XV)

Under N₂, sodium hydride (1.08 g, 0.027 mole, 60% oil dispersion) was added to a stirred solution of XIV (4.25 g, 0.024 mole) in dry DMSO (60 mL). The mixture was heated to 60° C. When the hydrogen evolution was complete, a solution of (S)-3-isopropyl-5-hydroxymethyloxazolid-2-one mesylate (5.69 g, 0.024 mole) in dry DMSO (60 mL) was added dropwise. The resulting mixture was stirred at 60° C. for 3 hours, then at ambient temperature overnight. After quenching in cold water, the product was extracted into CH₂ Cl₂. The washed and dried extract was evaporated to dryness to yield 8.54 g of the waxy crude product. This was purified by chromatography on silica gel, eluting with 95CHCl₃ --5CH₃ OH--0.5H₂ O, to obtain 2.75 g (36%) of XV; m.p. 148°-151° C. (EtOAc).

Analysis calculated for C₁₇ H₂₁ N₃ O₃ : C, 64.74; H, 6.71; N, 13.33. Found: C, 64.41; H, 6.86; N, 13.29.

Step D: (S)-4,5-Dibromo-2-{[p-(3-isopropyloxazolid-2-on-5-yl)methoxy]phenylmethyl}imidazole (XVI)

Compound XV (1.35 g, 4.3 mmoles) was dissolved in glacial HOAc (25 mL) and anhydrous powdered NaOAc (3.5 g, 43 mmoles) was added to give a thick stirred suspension. With cooling to 15° C., a solution of bromine (0.45 mL, 8.6 mmoles) in HOAc (10 mL) was added slowly dropwise over 1.5 hour. The resulting solution was concentrated under reduced pressure to a slush that was added to stirred ice water (400 mL). The gummy solid product was collected and dried over NaOH.

The crude dibromo compound (1.04 g, 2.2 mmoles) in dioxane (20 mL)--10% aqueous NaHSO₃ (50 mL) was stirred at reflux for 8 hours. After pouring the mixture into ice water (250 mL), the separated product was extracted into CHCl₃. The washed and dried extract was evaporated to dryness to yield 730 mg (43%) of XVI as a brown foam 'H NMR (CDCl₃) δ1.2 (6H, d), 3.7 (2H, s), 3.8 (7H, m), 6.8 (5H, m); IR (neat) 5.8μ (C=O).

Step E: (S)-4-Bromo-2-[p-(3-isopropylamino-2-hydroxypropoxy)phenylmethyl]imidazole (XVII)

A solution of XVI (700 mg, 1.8 mmoles) in EtOH (10 mL)--10% aqueous NaOH (10 mL) was stirred at reflux for 7 hours. After removal of the EtOH in vacuo, the residue was diluted with water and extracted with CHCl₃. The washed and dried CHCl₃ extract was evaporated to dryness to yield 250 mg of the crude product as a viscous yellow oil. This was purified by chromatography on silica gel, eluting with 95CHCl₃ --5CH₃ OH saturated with concentrated NH₄ OH. Trituration of the purified product afforded 215 mg (32%) of XVII; m.p. 125°-127° C. (Et₂ O).

Analysis calculated for C₁₆ H₂₂ BrN₃ O₂ : C, 52.18; H, 6.02; N, 11.41. Found: C, 52.38; H, 6.14; N, 11.06.

EXAMPLE 7 (S)-1-[4-(2-Thienyl)imidazol-2-yl]-2-p-[3-(3,4-dimethoxy-phenylethylamino)-2-hydroxypropoxy]phenyl ethane dihydrochloride dihydrate (XXI) Step A: 3-(p-Methoxyphenyl)propionamidine hydrochloride (XVIII)

Under N₂, a stirred solution of 3-(p-methoxyphenyl)propionitrile (11.2 g, 0.069 mole) in CH₃ OH (3 mL)-ether (5 mL)-dioxane (5 mL) was cooled in an ice bath while gaseous HCl was introduced until 4 g had been absorbed. The resulting mixture was held in a refrigerator. After 2 days, the solid mass was suspended in ether and the hygroscopic solid was collected and transferred quickly into a solution of ammonia (22 g) in CH₃ OH (100 mL) cooled to -78° C. The stirred mixture was allowed to warm to room temperature. After 24 hours, the solution was evaporated to dryness under reduced pressure. The solid residue was triturated with ether and collected to yield 11.8 g (79%) of XVIII; m.p. 123°-129° C. A sample triturated with acetone melted at 131°-133° C.

Anal. calc'd for C₁₀ H₁₄ N₂ O(+HCl): C, 55.94; H, 7.04; N, 13.05. Found: C, 55.20; H, 7.22; N, 13.05.

Step B: 2-(p-Methoxyphenylethyl)-4-(2-thienyl)imidazole (XIX)

Prepared as described in Example 5 for compound X except that XVIII was used in place of 4-methoxyphenylacetamidine. The crude product was purified by chromatography on silica gel, eluting with 2% CH₃ OH--CHCl₃ ; yield, 50% of XIX, 'H NMR (CDCl₃) δ2.9 (4H, s), 3.7 (3H, s), 6.9 (8H, m).

Step C: 2-(p-Hydroxyphenylethyl)-4-(2-thienyl)imidazole (XX)

A mixture of XIX (2.9 g, 0.01 mole), glacial HOAc (10 mL) and 48% HBr (35 mL) was stirred at reflux for 3 hours. The hot solution was decanted from the separated tar and chilled at 5°-10° C. overnight. The precipitated hydrobromide salt was collected, washed with Et₂ O, dissolved in H₂ O (100 mL), and the solution was made basic with saturated NaHCO₃ solution. The solid was collected, chromatographed on silica gel, and the product eluted with 95CHCl₃ --5CH₃ OH--0.5H₂ O to yield 0.725 g (27%) of XX; m.p. 165.5°-167° C. (50% CH₃ OH).

Analysis calculated for C₁₅ H₁₄ N₂ OS: C, 66.64; H, 5.22; N, 10.36. Found: C, 66.16; H, 5.20; N, 10.26.

Step D: (S)-1-[4-(2-Thienyl)imidazol-2-yl]-2-{p-[3-(3,4-dimethoxyphenylethylamino)-2-hydroxypropoxy]-phenyl}ethane dihydrochloride dihydrate (XXI)

Prepared as described previously in Example 4, except XX was used in place of VIII; 14% yield; m.p. 115°-120° C. (EtOH).

Analysis calculated for C₂₈ H₃₃ N₃ O₄ S(+2HCl+2H₂ O): C, 54.54; H, 6.38; N, 6.82. Found: C, 54.43; H, 6.28; N, 6.61.

EXAMPLE 8 (S)-2-{p-[3-(3,4-Dimethoxyphenylethylamino)-2-hydroxypropoxy]phenylmethyl}-4-acetylimidazole.hydrochloride (XXVIII) Step A: p-Methoxyphenylmethylamidoxime (XXII)

A mixture of H₂ NOH.HCl (74.7 g, 1.08 mol), K₂ CO₃ (60.1 g, 0.43 mol), p-methoxybenzylacetonitrile (64 g, 0.43 mol), EtOH (450 mL), and H₂ O (450 mL) was heated at 60°-70° C. with stirring. After 24 hours, the EtOH was removed under reduced pressure (20 mm) and the suspension filtered off to yield 50 g of XXII (65%); m.p. 108°-109° C. (C₆ H₅ CH₃).

Analysis calculated for C₉ H₁₂ N₂ O₂ : C, 59.98; H, 6.71; N, 15.54. Found: C, 59.99; H, 7.04; N, 15.50.

Step B: 4-Carboethoxy-2-(4-methoxyphenylmethyl)imidazole (XXIII)

A mixture of ethyl propiolate (20 g, 0.2 mol), XXII (36.7 g, 0.2 mol) and absolute EtOH (600 mL) was heated at reflux with stirring. After 18 hours, the reaction mixture was concentrated to dryness, the residue treated with diphenylether (200 mL), and the mixture heated at 180°-200° with stirring. After 1/2 hour, the brown-black reaction was cooled to 110° and poured into Pet-ether (2 L) with stirring. The solid was filtered off, the residue dissolved in CHCl₃ and chromatographed on alumina of activity grade II. The product was eluted with 15% Pet ether-CHCl₃ to yield 5.6 g (43%) of XXIII; m.p. 119°-21° C. (CH₃ CN).

Analysis calculated for C₁₄ H₁₆ N₂ O₃. C, 64.60; H, 6.20; N, 10.76. Found: C, 64.79; H, 6.19; N, 11.05.

Step C: 4-Carbamoyl-2-(4-methoxybenzylmethyl)imidazole (XXIV)

A mixture of XXIII (9.2 g, 0.035 mol), CH₃ OH (300 mL) and NH₃ (100 g) was heated in a sealed tube at 120° C. After 24 hours, the contents were removed and the mixture concentrated to dryness. The residue was triturated with Et₂ O to yield 7.9 g (97%) of XXIV; m.p. 218°-19° C. (CH₃ CN).

Analysis calculated for C₁₂ H₁₃ N₃ O₂ : C, 62.32; H, 5.66; N, 18.17. Found: C, 62.15; H, 5.90; N, 17.99.

Step D: 4-Cyano-2-(4-methoxyphenylmethyl)imidazole (XXV)

A mixture of XXIV (7.0 g, 0.031 mol) and POCl₃ (100 mL) was heated at reflux with stirring. After 6 hours, the reaction was stirred at room temperature overnight, concentrated to dryness, the residue flushed with toluene, treated with saturated Na₂ CO₃, extracted with 20% CH₃ OH--CHCl₃ (2X) and CHCl₃ (2X). The combined organic extracts were backwashed with saturated NaCl, dried, filtered and concentrated to dryness. The residue was triturated with Et₂ O to yield 4.9 g (77%) of XXV; m.p. 170°-1° C. (CH₃ CN).

Analysis calculated for C₁₂ H₁₁ N₃ O; high resolution MS 213.0903.

Step E: 4-Acetyl-2-(4-Methoxyphenylmethyl)imidazole (XXVI)

To a solution of XXV (2.11 g, 0.01 mol) in THF (50 mL) was added with stirring at room temperature methyl magnesium chloride (12 mL, 2.8M, 0.034 mol) in THF. After 24 hours, 3N HCl (50 mL) was added dropwise with stirring and the resulting mixture heated at reflux for 20 minutes. After cooling to room temperature, the solution was neutralized with solid Na₂ CO₃ and extracted with CHCl₃ (3X). The organic extracts were dried, filtered and concentrated to dryness to yield 2.35 g (100%) of XXVI; m.p. 147°-48° C. (CH₃ CN).

Analysis calculated for C₁₃ H₁₄ N₂ O₂ : C, 67.80; H, 6.13; N, 12.17. Found: C, 67.67; H, 6.28; N, 12.28.

Step F: 4-Acetyl-2-(4-hydroxyphenylmethyl)imidazole (XXVII)

A solution of XXVI (2.2 g, 0.01 mol), AcOH (10 mL) and 48% HBr (40 mL) was heated at reflux. After 24 hours, the solution was concentrated to dryness, neutralized with NaHCO₃ to pH 8.5 and the mixture stirred at room temperature. The suspension was concentrated to dryness mixed with CH₃ OH (100 mL) and silica gel (20 g) and concentrated to dryness. The solid was placed on a silica gel column and the product eluted with 5% CH₃ OH--CHCl₃ to yield 1.7 g (81%) of XXVII; m.p. 229°-31° C. (CH₃ CN).

Analysis calculated for C₁₂ H₁₂ N₂ O₂ : C, 66.65; H, 5.60; N, 12.96. Found: C, 66.67; H, 5.70; N, 13.31.

Step G: (S)-2-p-[3,4-Dimethoxyphenylethylamino)-2-hydroxypropoxy]phenylmethyl-4-acetylimidazole hydrochloride (XXVIII)

Compound XXVIII was prepared as described in Example 4 except XXVII was used in place of VIII. The compound was chromatographed on silica gel and the product eluted with 10% CH₃ OH--CHCl₃ to yield 75 mg of XXVIII (2.4%); m.p. 191°-3° C. (CH₃ CN).

Analysis calculated for C₂₅ H₃₁, N₃ O₅.HCl (HCl came from CHCl₃): C, 61.28; H, 6.58; N, 8.58. Found: C, 60.96; H, 6.76; N, 8.34.

EXAMPLE 9 (S) 3-[3,4-Dimethoxyphenylethylamino]-2-hydroxy-1-[4-[2-imidazolylmethoxymethyl]phenoxy]propane (XXXII) Step A: 2-Carbomethoxy-1-tritylimidazole (XXIX)

Compound XXIX was prepared as described for the preparation of 3-carboethoxy-1-tritylimidazole by Kirk (J. Org. Chem., (1978) 43, 4381); 23% yield; m.p. 186°-8° C. (EtOH).

Analysis calculated for C₂₄ H₂₀ N₂ O: N, 7.6; C, 78.27; H, 5.47 Found: N, 7.95; C, 77.96; H, 5.52.

Step B: 2-Hydroxymethyl-1-tritylimidazole (XXX)

A solution of XXIX (1.1 g, 0.003 mol) in dry THF (10 mL) was added dropwise with stirring at 0°-4° C. to a suspension of LAH (0.14 g, 0.0036 mol) in dry THF (10 mL). The mixture was stirred at room temperature, further cooled, H₂ O (0.13 mL) added, followed by 10% NaOH (0.2 mL) and finally H₂ O (0.33 mL). The mixture was stirred at room temperature for 30 minutes, then at 0° C. for 1 hour, filtered and the collected solid, washed with THF, hot EtOH (2x) and CHCl₃. The combined filtrates were concentrated to dryness. The residue was triturated with hot absolute EtOH to yield 0.7 g (69%) of XXX; m.p. 243°-4°.

Analysis calculated for C₂₃ H₂₀ N₂ 1/2H₂ O: C, 79.06; H, 6.06; N, 8.02 Found: C, 79.16; H, 5.88; N, 8.26

Step C: (S) 3-(3,4-Dimethoxyphenylethyl)-5-(4-hydroxymethylphenoxymethyl)-oxazoline-2-one (XXXI)

To a stirred solution of 4-hydroxybenzyl-alcohol (4.1 g, 0.0033 mol) in DMSO (75 mL), NaH (60%) oil dispersion, 1.32 g, 0.0033 mol) was added under N₂. The mixture was heated at 60° C. for 15 minutes and then (S)-3-(3,4-dimethoxyphenyl)ethyl-5-(hydroxymethyl)oxazolid-2-one mesylate (10.8 g, 0.003 mol) was added. The mixture was stirred at 60° C. for 2 hours, then poured in H₂ O and the aqueous extracted with EtOAc (2X). The organic extracts were washed with saturated Na₂ CO₃, 0.1N HCl, H₂ O, filtered and concentrated to dryness. The residue was chromatographed on silica gel eluting with CHCl₃ -CH₃ OH--H₂ O (90:5:0.5) to yield 5.0 g (43%) of XXXI.

Analysis calculated for C₂₁ H₂₅ NO₆.1/2H₂ O: N, 3.53; C, 63.62; H, 6.61 Found: N, 3.45; C, 63.62; H, 6.46.

Step D: (S) 3-[3,4-Dimethoxyphenylethylamino]-2-hydroxy-1-[4-[2-imidazolylmethoxymethyl]phenoxy]propane (XXXII)

Compound XXXI (2.71 g, 0.007 mL) was dissolved in CH₂ Cl₂ (25 mL), cooled and Et₃ N (0.78 g, 0.0077 mol) added. To the cooled solution, methanesulfonyl chloride (0.88 g, 0.0077 mol) in CH₂ Cl₂ (2 mL) was added and stirred at room temperature. After 3 hours another portion of methanesulfonylchloride (0.09 g, 0.007 mol) was added. After 1 hour, the reaction was poured in H₂ O (25 mL) containing K₂ CO₃ (1 g) and the organic extracted with CH₂ Cl₂ (3X). The aqueous extracts were washed with H₂ O, 0.5N, HCl, H₂ O, dried, filtered and concentrated to dryness. The residue was dissolved in dry DMSO (20 mL) and added with stirring at room temperature to a solution of XXX (1.7 g, 0.005 mol) and NaH (60% oil dispersion, 0.22 g, 0.0055 mol) in DMSO (20 mL). After 2 hours, another portion of NaH (0.2 g) was added and stirred at room temperature for an additional 2 hours. The solution was then poured in H₂ O and the aqueous extracted with EtOAc (2X). The organic extracts were dried, filtered and concentrated to dryness. The residue was treated with CH₃ OH (25 mL) and 40% NaOH (6 mL) and the solution heated at reflux. After 2 hours, the solution was poured into H₂ O. The aqueous layer was extracted with CHCl₃ (3X) and the organic extracts dried, filtered and concentrated to dryness. The residue was treated with CH₃ OH (50 mL) and HOAc (2.5 mL) and heated at reflux for 2 hours. The reaction was then concentrated to dryness, 0.1N HCl (75 mL) added, the aqueous extracted with CHCl₃ (3X) and the organic extracts discarded. The aqueous solution was basified to pH 10 with saturated Na₂ CO₃ and extracted with CHCl₃ (2X). The organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel eluting with CHCl₃ saturated with NH₃ and CHCl₃ --CH₃ OH--NH₄ OH (70:5:0.5 to 90:10:1) to yield XXXII; 13% yield.

Analysis calculated for C₂₄ H₃₁ N₃ O₅ : N, 9.52; C, 65.29; H, 7.08. Found: N, 8.94; C, 64.95; H, 6.94.

EXAMPLE 10 (S) 3-(3,4-Dimethoxyphenylethylamino)-2-hydroxy-1-[4-(2-imidazolylmethoxy)phenoxy]propane (XXXV) Step A: 3-(3,4-Dimethoxyphenylethyl)-5-(4-hydroxyphenoxymethyl)oxazolid-2-one (XXXIII)

To a solution of 4-benzyloxyphenol (6.6 g, 0.0033 mol) in DMSO (75 mL) was added under N₂ with stirring NaH (60% oil dispersion, 1.32 g, 0.0033 mmol). The mixture was stirred for 15 minutes and then (S)-3-(3,4-dimethoxyphenyl)ethyl-5-(hydroxymethyl)oxazolid-2-one mesylate (10.78 g, 0.003 mol) added. The mixture was heated at 60° C. for 1 hour and then the DMSO was removed under reduced pressure (2 mm). The residue was partitioned between H₂ O and EtOAc (3X). The organic extracts were washed with dilute Na₂ CO₃, 0.2N HCl, H₂ O, dried, filtered and cooled to yield 14.5 g of crude product. The alcohol (4.63 g, 0.001 mol) was suspended in 4.4% HCO₂ H in CH₃ OH (100 mL) under N₂, 10% Pd on C (0.93 g) added and the mixture stirred at room temperature overnight. The suspension was filtered and the filtrate evaporated to dryness to yield 1.7 g (96%) of XXXIII; ¹ H NMR (CDCl₃) δ 2.8 (2H, t, J=7), 3.45 (4H, m), 3.77 (3H, s), 3.8 (3H, s), 3.85 (2H, d), 4.7 (1H, m), 6.75 (7H, m).

Step B: (S) 5-[4-[2-(1-Benzyl)imidazolylmethyloxy]phenoxymethyl]-3-(3,4-dimethoxyphenylethyl)oxazoline-2-one (XXXIV)

Compound XXXIII (1.4 g, 0.00375 mol) was dissolved in dry DMSO (15 mL) and NaH (60% oil dispersion, 0.3 g, 0.0075 mol) added with stirring. After 15 minutes, 1-benzyl-2-chloromethylimidazole (0.91 g, 0.0025 mol) was added and the mixture stirred at room temperature for 4 hours. The reaction mixture was poured in H₂ O and the aqueous extracted with EtOAc (2X). The organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel eluting with CHCl₃ --CH₃ OH--H₂ O (80:20:2) to yield 0.84 g (41%) of XXXIV. ¹ H NMR (CDCl₃) 2.8 (2H, t, J=7), 3.50 (4H, m), 3.77 (3H, s), 3.8 (3H, s), 3.9 (2H, d), 4.7 (1H, m), 5.0 (2H, s), 5.2 (2H, s), 6.7-7.4 (14H, m).

Step C: (S) 3-(3,4-Dimethoxyphenylethyl)-2-hydroxy-1-[4-(2-imidazolylmethoxy)phenoxy]propane (XXXV)

Compound XXXIV (0.82 g, 0.0015 mol) was treated with CH₃ OH (25 mL) and 40% NaOH (6 mL) and the mixture heated at reflux for 3 hours. The reaction was poured into H₂ O and extracted with CHCl₃ (2X). The organic extracts were washed with H₂ O, dried, filtered and concentrated to dryness. The residue (0.62 g, 0.0012 mol) was suspended in liquid NH₃ (20 mL) and Na (0.17 g, 0.006 mol) added. After the solution turned blue, the mixture was stirred for 15 minutes and then solid NH₄ Cl (0.55 g) added, NH₃ was allowed to evaporate, H₂ O was added and the pH adjusted to 1 by the addition of concentrated HCl (˜0.3 mL). The aqueous solution was extracted with CHCl₃ (2X), adjusted to pH>10 with saturated Na₂ CO₃. The aqueous solution was extracted with CHCl₃ (2X), the organic extracts dried, filtered and concentrated to dryness. The crude product was chromatographed on silica gel using a linear gradient elution with CHCl₃ (1 liter) and CHCl₃ --CH₃ OH--H₂ O (60:40:4) containing 2.5 mL of concentrated NH₄ OH to yield XXXV; 25% yield, m.p. 129°-30° C. (trituration with CH₃ CN--Et₂ O).

Analysis calculated for C₂₃ H₂₉ N₃ O₅ : N, 9.83; C, 64.62; H, 6.84. Found: N, 9.61; C, 64.54; H, 6.70

Using the procedures and methods described in the foregoing Methods and Examples additional compounds of Formula I can be prepared as set forth in Table I below wherein Ph denotes phenyl and DMPE denotes 3,4-dimethoxyphenylethyl:

                                      TABLE I                                      __________________________________________________________________________      ##STR23##                                           I                         R     R.sub.1  R.sub.2                                                                           m X  n R.sub.3   R.sub.4                                                                              R.sub.5                               __________________________________________________________________________     (a)                                                                               H  H        H  1 O  1                                                                                 ##STR24##                                                                               OH    DMPE                                  (b)                                                                               "  "        "  " CH.sub.2                                                                          0 "         "     "                                     (c)                                                                               "  Br       "  0 "  " "         "     C.sub.6 H.sub.5                       (d)                                                                               "  "        "  1 "  " "         "     CH.sub.2 CH.sub.2 CH.sub.3            (e)                                                                               "                                                                                  ##STR25##                                                                              "  " "  "                                                                                 ##STR26##                                                                               "     DMPE                                  (f)                                                                               "  Br       "  2 "  "                                                                                 ##STR27##                                                                               "     "                                     (g)                                                                               "                                                                                  ##STR28##                                                                              "  0 CH.sub.2                                                                          " "         "     (CH.sub.3).sub.2 CH                   (h)                                                                               "  H.sub.3 COCH.sub.2                                                                      "  " "  "                                                                                 ##STR29##                                                                               "     DMPE                                  (i)                                                                               "  Br       CH.sub.3                                                                          " "  "                                                                                 ##STR30##                                                                               "                                                                                     ##STR31##                            (j)                                                                               "  CN       H  2 O  1 "         "                                                                                     ##STR32##                            (k)                                                                               CH.sub.3                                                                           ##STR33##                                                                              "  1 "  0                                                                                 ##STR34##                                                                               "     (CH.sub.3).sub.3 C                    (l)                                                                               Br Br       H  0 CH.sub.2                                                                          0                                                                                 ##STR35##                                                                               OH                                                                                    ##STR36##                            (m)                                                                               H                                                                                  ##STR37##                                                                              "  3 "  "                                                                                 ##STR38##                                                                               "                                                                                     ##STR39##                            (n)                                                                               "                                                                                  ##STR40##                                                                              "  0 "  0                                                                                 ##STR41##                                                                               "     DMPE                                  (o)                                                                               "  CO.sub.2 H                                                                              "  " "  "                                                                                 ##STR42##                                                                               "                                                                                     ##STR43##                            (p)                                                                               "  CO.sub.2 Et                                                                             "  2 O  2 "                                                                                         ##STR44##                                                                           DMPE                                  (q)                                                                               "  CH(CH.sub.3).sub.2                                                                      "  " S  " "         OH    (CH.sub.2).sub.2 OCH.sub.2                                                     CH.sub.3                              (r)                                                                               "  C(CH.sub.3).sub.3                                                                       "  1 O  "                                                                                 ##STR45##                                                                               "                                           (s)                                                                               "                                                                                  ##STR46##                                                                              "  2 "  0                                                                                 ##STR47##                                                                               "     DMPE                                  (t)                                                                               "                                                                                  ##STR48##                                                                              "  " "  "                                                                                 ##STR49##                                                                               "     "                                     (u)                                                                               "                                                                                  ##STR50##                                                                              "  1 "  "                                                                                 ##STR51##                                                                               "     "                                     (v)                                                                               "                                                                                  ##STR52##                                                                              "  0 CH.sub.2                                                                          0                                                                                 ##STR53##                                                                               "     "                                     (w)                                                                               "  Br       "  1 "  "                                                                                 ##STR54##                                                                               "                                                                                     ##STR55##                            (x)                                                                               "  H        "  0 "  " "         "                                                                                     ##STR56##                            (y)                                                                               "  CH.sub.3 "  " "  " "         "                                                                                     ##STR57##                            (z)                                                                               CH.sub.3                                                                          "        "  " "  " "         "                                                                                     ##STR58##                            (aa)                                                                              H  "        "  " "  " "         "     CH.sub.2 CH.sub.2 SCH.sub.2                                                    CH.sub.3                              (bb)                                                                              H                                                                                  ##STR59##                                                                              H  2 CH.sub.2                                                                          2                                                                                 ##STR60##                                                                               OH    (CH.sub.3).sub.2 CH                   (cc)                                                                              "                                                                                  ##STR61##                                                                              "  " "  1 "         "                                                                                     ##STR62##                            (dd)                                                                              "                                                                                  ##STR63##                                                                              "  3 O  "                                                                                 ##STR64##                                                                                ##STR65##                                                                           DMPE                                  (ee)                                                                              "  CF.sub.3 "  " "  0                                                                                 ##STR66##                                                                               OH    (CH.sub.3).sub.2 CH                   (ff)                                                                              "                                                                                  ##STR67##                                                                              CH.sub.3                                                                          " S  1 "         "     DMPE                                  (gg)                                                                              "  Cl       H  2 "  2 "         "                                                                                     ##STR68##                            (hh)                                                                              Cl CH.sub.3 "  1 CH.sub.2                                                                          1 "         "                                                                                     ##STR69##                            (ii)                                                                              H  "        "  " "  0 "         "                                                                                     ##STR70##                            __________________________________________________________________________

In evaluating the β-blocking effectiveness of the present compounds, it was noted that the compounds exhibit cardioselectivity; that is, the compounds are more effective in reducing the heart rate effects of isoproterenol than they are in blocking the isoproterenol effects on the bronchi. Expressed in different terms, a smaller amount of a compound of the invention is required to block isoproterenol-induced elevation in heart rate than is required to block the isoproterenol-induced relaxation of the bronchi. This cardioselectivity factor can be expressed as the ratio of ED₅₀ for pulmonary effect (β₂):ED₅₀ for cardiac effect (β₁). Where the β₂ :β₁ ratio is over 1, then the compound would be considered to have cardioselective activity.

Compounds of the invention which were tested and found to have β₂ :β₁ ratios greater than 1 are shown in Table II below wherein the in vitro results obtained were determined according to the procedure described by Baldwin et al., J. Med. Chem., 26, 956-7 (1983):

                  TABLE II                                                         ______________________________________                                         Compounds Having B.sub.2 :B.sub.1 > 1                                          Example                                                                               Compound                 B.sub.2 :B.sub.1                               ______________________________________                                         1      (S)--2-{p-[3-(3,4-dimethoxyphenethyl-                                                                   144                                                   amino)-2-hydroxypropoxy]phenylmethyl}-                                         4-methylimidazole                                                       2      (S)--2-[p-(3-t-butylamino-2-hydroxy-                                                                    10.5                                                  propoxy)phenylmethyl]-4-(2-thienyl)-                                           imidazole dihydrogen maleate salt                                       3      (S)--2-[p-(3-t-butylamino-2-hydroxy-                                                                    3.3                                                   propoxy)phenylmethyl]-4-methylimidazole                                 4      (S)--1-(4-bromoimidazol-2-yl)-2-{p-[3-(3,4-                                                             398                                                   dimethoxyphenylethylamino)-2-hydroxy-                                          propoxy]phenyl}ethane                                                   5      (S)--2-{p-[3-(3,4-dimethoxyphenylethyl)-                                                                >10,000                                               amino)-2-hydroxypropoxy]phenylmethyl}-                                         4-(2-thienyl)imidazole                                                  6      (S)--4-bromo-2-[p-(3-isopropylamino-2-                                                                  7.8                                                   hydroxypropoxy)phenylmethyl]imidazole                                   7      (S)--1-[4-(2-thienyl)imidazol-2-yl]-2-{p-[3-                                                            1280                                                  (3,4-dimethoxyphenylethylamino)-2-hydroxy-                                     propoxy]phenyl}ethane                                                   8      (S)--2-{p-[3-(3,4-dimethoxyphenylethyl-                                                                 >9333                                                 amino)-2-hydroxypropoxy]phenylmethyl}-                                         4-acetylimidazole                                                       9      (S)--3-[3,4-dimethoxyphenylethyl-                                                                       302                                                   amino]-2-hydroxy-1-[4-[2-imidazolyl-                                           methoxymethyl]phenoxy]propane                                           10     (S)--3-(3,4-dimethoxyphenylethyl-                                                                       209                                                   amino)-2-hydroxy-1-[4-(2-imidazolyl-                                           methoxy)phenoxy]propane                                                 ______________________________________                                    

As previously mentioned, the β-adrenergic blocking agents of the invention are devoid of intrinsic sympathomimetic activity (ISA); i.e., they are devoid of partial agonism causing a greater slowing of heart rate than β-blockers with partial agonism. Compounds which exhibit this feature should be more efficacious in the treatment of angina, a condition responsive to agents with decreased oxygen consumption. Since bradycardia (slowing of heart rate) is a major determinant of oxygen consumption, β-blockers that exhibit ISA should produce less of a decrement in oxygen consumption and also cause a sharp decline in blood pressure due to stimulation of vascular β₂ -receptors which subserve vasodilation. Thus, β-blocking agents which are devoid of ISA would be expected to produce a more gradual decline in blood pressure.

Compounds of the invention were tested for ISA using the following method:

Male Sprague-Dawley rats weighing 250 to 350 grams were pretreated with reserpine, 5 mg/kg i.p., approximately 18 hours prior to the experiment. Dial-Urethane at 1 mg/kg i.p. was used for anesthesia. The vagi were cut and a tracheal tube was inserted. Blood pressure was recorded from an indwelling arterial (carotid artery) catheter and the heart rate was calculated from the blood pressure tracing. Mean arterial pressure and heart rate were recorded at 0, 2, 4, 8, 15, 30, 45 and 60 minutes. Compounds were dissolved in distilled H₂ O or 1N HCl and administered intravenously over two minutes. For compounds producing bell-shaped curves, only the ascending segment of the dose response was used to calculate ED₅₀ 's.

The results of these tests are listed below in Table III wherein "+" indicates the compounds tested were devoid of ISA and "-" means the compounds tested exhibited ISA.

                  TABLE III                                                        ______________________________________                                                Compound of                                                                    Example  ISA                                                            ______________________________________                                                1        +                                                                     5        +                                                                     6        +                                                                     7        +                                                                     8        +                                                              ______________________________________                                     

What is claimed is:
 1. A compound having the formula: ##STR71## R and R₁ are independently: hydrogen;C₁ -C₈ linear or branched alkyl; fluoro, bromo, chloro; heteroaryl groups having 5-ring atoms selected from furyl, thienyl and N--C₁ -C₈ -lower alkylpyrrolyl; carboalkoxy wherein the alkyl group has up to 8 carbon atoms; CF₃ ; carbamoyl; cyano; ##STR72## wherein R_(a) is hydrogen or C₁ -C₈ alkyl; unsubstituted or substituted aryl of C₆ having 1-5 substituents selected from fluoro, bromo, chloro, C₁ -C₈ linear or branched alkly, or C₁ -C₈ alkoxy; heteroaryl groups having 6-ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl; R₂ is hydrogen; C₁ -C₈ linear or branched alkyl; R₃ is unsubstituted or substituted arylene of C₆ or C₁₀ having 1-2 substituents selected from halo, C₁ -C₈ alkoxy, alkenyloxy having up to 8 carbon atoms; C₁ -C₈ linear or branched alkyl; cyano, ##STR73## wherein R_(a) is as defined above; R₄ is hydroxy; R₅ is C₃ -C₅ cycloalkyl; C₁ -C₈ linear or branched alkyl; unsubstituted or substituted aralkyl wherein the alkyl is linear or branched C₁ -C₈ and the aryl is C₆ -C₁₀ having 1-2 substituents selected from C₁ -C₈ alkoxy, hydroxy, fluoro, bromo, chloro, C₁ -C₈ alkyl; heteroaryl having 6-ring atoms containing 1-2N heteroatoms; X is oxygen or CH₂ ; and, m an n are independently 0-2 provided that at least one of m or n is
 1. 2. A compound of claim 1 wherein:R and R₁ are independently: hydrogen; C₁ -C₈ linear or branched alkyl; fluoro, bromo, chloro; heteroaryl groups having 5-ring atoms selected from furyl, thienyl and N--C₁ -C₈ lower alkylpyrrolyl; carboalkoxy wherein the alkyl group has up to 8 carbon atoms; CF₃ ; ##STR74## wherein R_(a) is C₁ -C₃ alkyl; R₂ is hydrogen; R₃ is 1,4-phenylene; R₄ is hydroxy; R₅ is C₃ -C₅ cycloalkyl; C₁ -C₈ linear or branched alkyl; unsubstituted or substituted aralkyl wherein the alkyl is linear or branched C₁ -C₈ and the aryl is C₆ having 1-2 C₁ -C₈ alkoxy substituents; X is CH₂ ; and, m and n are independently zero or
 1. 3. A compound according to claim 1 which is (S)-2-p-[3-(3,4-dimethoxyphenylethylamino)-2-hydroxypropoxy]phenylmethyl-4-methylimidazole.
 4. A compound according to claim 1 which is (S)-2-[p-(3-t-butylamino-2-hydroxypropoxy)phenyl-methyl]-4-(2-thienyl)imidazole.
 5. A compound according to claim 1 which is (S)-2-[p-(3-t-butylamino-2-hydroxypropoxy)phenyl-methyl]-4-methylimidazole
 6. A compound according to claim 1 which is (S)-1-(4-bromoimidazol]-2-yl)-2-p-[3-(3,4-dimethoxyphenylethylamino)-2-hydroxypropoxy]phenyl ethane.
 7. A compound according to claim 1 which is (S)-2-p-[3-(3,4-dimethoxyphenylethamino)-2-hydroxypropoxy]phenylmethyl-4-(2-thienyl)-imidazole.
 8. A compound according to claim 1 which is (S)-4-bromo-2-[p-(3-isopropylamino-2-hydroxypropoxy)phenylmethyl]imidazole.
 9. A compound according to claim 1 which is (S)-1-[4-(2-thienyl)imidazol-2-yl]-2-p-[3-(3,4-dimethoxyphenylethylamino)-2-hydroxypropoxy]phenyl ethane.
 10. A compound according to claim 1 which is (S)-2-p-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]phenylmethyl-4-acetylimidazole.
 11. A compound according to claim 1 which is (S)-3-[3,4-dimethoxyphenylethylamino]-2-hydroxy-1-[4-[2-imidazolylmethoxymethyl]phenoxy propane
 12. A compound according to claim 1 which is (S)-3-(3,4-dimethoxyphenylethylamino)-2-hydroxy-1-[4-(2-imidazolylmethoxy)phenoxy]propane. 